A Novel Monoclonal Antibody Against DOG1 is a Sensitive and Specific Marker for Gastrointestinal Stromal Tumors

Department of Pathology, Stanford University Medical Center, Stanford, CA 94305, USA.
American Journal of Surgical Pathology (Impact Factor: 5.15). 03/2008; 32(2):210-8. DOI: 10.1097/PAS.0b013e3181238cec
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Gastrointestinal stromal tumors (GIST) occur primarily in the wall of the intestine and are characterized by activating mutations in the receptor tyrosine kinases genes KIT or PDGFRA. The diagnosis of GIST relies heavily on the demonstration of KIT/CD117 protein expression by immunohistochemistry. However, KIT expression is absent in approximately 4% to 15% of GIST and this can complicate the diagnosis of GIST in patients who may benefit from treatment with receptor tyrosine kinase inhibitors. We previously identified DOG1/TMEM16A as a novel marker for GIST using a conventional rabbit antipeptide antiserum and an in situ hybridization probe. Here, we describe 2 new monoclonal antibodies against DOG1 (DOG1.1 and DOG1.3) and compare their staining profiles with KIT and CD34 antibodies on 447 cases of GIST. These included 306 cases with known mutational status for KIT and PDGFRA from a molecular consultation service. In addition, 935 other mesenchymal tumors and 432 nonsarcomatous tumors were studied. Both DOG1 antibodies showed high sensitivity and specificity for GIST, with DOG1.1 showing some advantages. This antibody yielded positive staining in 370 of 425 (87%) scorable GIST, whereas CD117 was positive in 317 of 428 (74%) GIST and CD34 in 254 of 430 (59%) GIST. In GIST with mutations in PDGFRA, 79% (23/29) showed DOG1.1 immunoreactivity while only 9% (3/32) and 27% (9/33) stained for CD117 and CD34, respectively. Only 1 of 326 (0.3%) leiomyosarcomas and 1 of 39 (2.5%) synovial sarcomas among the 935 soft tissue tumors examined showed positive immunostaining for DOG1.1. In addition, DOG1.1 immunoreactivity was seen in fewer cases of carcinoma, melanoma, and seminoma as compared with KIT.

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    • "Recently, one of which was focused on the most important marker is DOG1. In the study of Espinosa et al in 425 cases they showed that DOG1 has a high specificity and sensitivity in the diagnosis of GIST and DOG1 positivity was 87% and 74% positiveness for c-kit [4]. West et al, they studied on 149 cases and showed that DOG1 positivity was 97.8%, the c-kit positivity was 94% in GIST [5] in the study of Miettinen et al at 1168 GIST cases DOG1 positivity was 94.8%, the c-kit positivity was 94.9%. "
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    ABSTRACT: Aim: Gastrointestinal stromal tumor is the most common mesenchymal neoplasia in the gastrointestinal tract and has a broad spectrum of pathological patterns and also clinical features changing from benign to malignant. Although the well-characterized parameters to predict the outcome have been the size and the mitotic index of the tumor in the patients with early-staged disease, bulky recurrent or metastatic tumor, resistance to medical treatment and mutation analysis are the prognostic factors for advanced stage-GIST. The aim of this study is to investigate new and more practical tissue markers, such as DOG1 and Ki-67 to specify the GIST diagnosis and also to predict the outcome in GIST patients with both localized and advanced staged disease. Methods: For the last 14 years, from 1999 to 2013, 111 patients with a histopathological GIST diagnosis from the hospital files were enrolled to the study. In their parafin-embedded tissue samples, DOG1 and Ki-67 expressions were evaluated with immunohistochemisty by two independent pathologists from Cukurova University Medical Faculty. Patients were divided into two groups, the patients with localized disease treated by surgery and the patients with advanced/metastatic disease. DOG1 and Ki-67 expressions were corelated with other diagnostic and prognostic histopathological markers and also the clinical outcome in these two group of patients. Results: The specificity and the sensitivity of DOG1 in GIST diagnosis was found 94 and 43%, respectively. DOG1 expression was especially important in the diagnosis of c-kit negative cases. Although Ki-67 was not found a statistically significant prognostic factor for overall survival, it was strongly corelated with mitotic index which is a well-known standart prognostic factor for localized disease. Discussion: DOG1 seems to be an important diagnostic tool for clinically suspected GIST diagnosis in both advanced or early staged patients whose tumours are c-kit expression negative. On the other hand, Ki-67 can be a stronger candidate for prognostic factor instead of mitotic index to identify the proliferative cells out of mitotic phase but this statement needs be prospectively validated on studies with large number of patients.
    International Journal of Clinical and Experimental Medicine 08/2014; 7(7):1914-22. · 1.28 Impact Factor
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    • "Looking more specifically at discordant cases, there were fewer discrepancies related to GIST compared with 2005. Previously, pitfalls in the diagnosis of GIST existed due to inconsistent staining with CD34 and CD117 [13, 14], but now there is increasing familiarity with this neoplasm and its pattern of immunohistochemical staining, including the use of DOG1 antibody [15] as recommended in national guidelines. In contrast, there was no significant decrease in discrepancies involving leiomyosarcomas, fibromatosis, and liposarcomas, which were among the commonest causes of discrepancy. "
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    ABSTRACT: Introduction. Soft tissue tumour pathology is a highly specialised area of surgical pathology, but soft tissue neoplasms can occur at virtually all sites and are therefore encountered by a wide population of surgical pathologists. Potential sarcomas require referral to specialist centres for review by pathologists who see a large number of soft tissue lesions and where appropriate ancillary investigations can be performed. We have previously assessed the types of diagnostic discrepancies between referring and final diagnosis for soft tissue lesions referred to our tertiary centre. We now reaudit this 6 years later, assessing changes in discrepancy patterns, particularly in relation to the now widespread use of ancillary molecular diagnostic techniques which were not prevalent in our original study. Materials and Methods. We compared the sarcoma unit's histopathology reports with referring reports on 348 specimens from 286 patients with suspected or proven soft tissue tumours in a one-year period. Results. Diagnostic agreement was seen in 250 cases (71.8%), with 57 (16.4%) major and 41 (11.8%) minor discrepancies. There were 23 cases of benign/malignant discrepancies (23.5% of all discrepancies). 50 ancillary molecular tests were performed, 33 for aiding diagnosis and 17 mutational analyses for gastrointestinal stromal tumour to guide therapy. Findings from ancillary techniques contributed to 3 major and 4 minor discrepancies. While the results were broadly similar to those of the previous study, there was an increase in frequency of major discrepancies. Conclusion. Six years following our previous study and notably now in an era of widespread ancillary molecular diagnosis, the overall discrepancy rate between referral and tertiary centre diagnosis remains similar, but there is an increase in frequency of major discrepancies likely to alter patient management. A possible reason for the increase in major discrepancies is the increasing lack of exposure to soft tissue cases in nonspecialist centres in a time of subspecialisation. The findings support the national guidelines in which all suspected soft tissue tumour pathology specimens should be referred to a specialist sarcoma unit.
    Sarcoma 08/2014; 2014:686902. DOI:10.1155/2014/686902
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    • "A variety of spindle cell tumors exhibit KIT positivity, including mesothelioma [24], leiomyosarcoma [24], clear cell sarcoma [24], rhabdomyosarcoma [24], synovial sarcoma [24], angiomyolipoma [25,26], bladder urothelial carcinoma [24,27], and malignant melanoma [27]. Therefore, KIT immunopositivity alone cannot differentially diagnose a GIST among spindle cell tumors. "
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    ABSTRACT: Inflammatory myofibroblastic tumors (IMTs) and gastrointestinal stromal tumors (GISTs) are both spindle cell tumors, and occur rarely in the wall of the urinary bladder. In general, immunostaining allows differentiation of IMTs and GISTs. Most IMTs are positive for anaplastic lymphoma kinase (ALK) and negative for KIT, whereas most GISTs are ALK-negative and KIT-positive. Here, we describe a case of a spindle cell tumor in the wall of the urinary bladder. The spindle cells were positive for both ALK and KIT, and it was thus difficult to determine whether the tumor was an IMT or a GIST. We eventually diagnosed an IMT, because ALK gene rearrangement was confirmed by fluorescent in-situ hybridization. Cytoplasmic staining for KIT and the absence of other GIST markers, including DOG1 and platelet-derived growth factor alpha, indicated that the tumor was not a GIST. Therefore, IMTs should be included in the differential diagnosis of spindle cell tumors, even those that are KIT-positive.
    World Journal of Surgical Oncology 06/2014; 12(1):186. DOI:10.1186/1477-7819-12-186 · 1.41 Impact Factor
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